Mast cells participate in the development of diastolic dysfunction in diabetic obese mice

Abstract

Rational: Heart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic issue. However, to date, its pathophysiology remains poorly understood. Objective: Our goal was to investigate the role of microvessel disease in the pathophysiology of diastolic dysfunction. Findings: To do so, we used Leptin receptor deficient (Lepr db/db ) female mice as a model of diastolic dysfunction. In these mice, the increased end diastolic pressure (EDP) signing diastolic dysfunction is associated with vascular leakage, endothelial cell activation and leucocyte infiltration. Strikingly, a RNA sequencing analysis of the cardiac vascular fraction of both Lepr db/db and control female mice confirmed endothelial dysfunction and systemic inflammation but also revealed a strong increase in several mast cell markers (notably FceR1a, Tryptase and Chymase). We then histologically confirmed an accumulation of activated mast cells in the heart of Lepr db/db mice. Importantly, mast cell degranulation inhibition reduced EDP, vascular leakage and leucocyte infiltration in Lepr db/db mice. Conclusion: Mast cells play a critical role in the development of cardiac microvessel disease and diastolic dysfunction.